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WO2012041519A2 - Élastomères photoréticulants pour le prototypage rapide - Google Patents

Élastomères photoréticulants pour le prototypage rapide Download PDF

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Publication number
WO2012041519A2
WO2012041519A2 PCT/EP2011/004908 EP2011004908W WO2012041519A2 WO 2012041519 A2 WO2012041519 A2 WO 2012041519A2 EP 2011004908 W EP2011004908 W EP 2011004908W WO 2012041519 A2 WO2012041519 A2 WO 2012041519A2
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WO
WIPO (PCT)
Prior art keywords
photocrosslinkable
component
preferred
organ
acrylate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2011/004908
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German (de)
English (en)
Other versions
WO2012041519A3 (fr
Inventor
Hartmut Krüger
Wolfdietrich Meyer
Michael Wegener
Careen Graf
Oliver Refle
Sascha Engelhardt
Melanie Dettling
Kirsten Borchers
Günter Tovar
Elke Bremus-Köbberling
Christian Schuh
Esther Novosel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fraunhofer Gesellschaft zur Foerderung der Angewandten Forschung eV
Original Assignee
Fraunhofer Gesellschaft zur Foerderung der Angewandten Forschung eV
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Filing date
Publication date
Priority claimed from DE102011012480A external-priority patent/DE102011012480A1/de
Application filed by Fraunhofer Gesellschaft zur Foerderung der Angewandten Forschung eV filed Critical Fraunhofer Gesellschaft zur Foerderung der Angewandten Forschung eV
Priority to EP11771021.0A priority Critical patent/EP2621714A2/fr
Publication of WO2012041519A2 publication Critical patent/WO2012041519A2/fr
Publication of WO2012041519A3 publication Critical patent/WO2012041519A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • G—PHYSICS
    • G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
    • G03F—PHOTOMECHANICAL PRODUCTION OF TEXTURED OR PATTERNED SURFACES, e.g. FOR PRINTING, FOR PROCESSING OF SEMICONDUCTOR DEVICES; MATERIALS THEREFOR; ORIGINALS THEREFOR; APPARATUS SPECIALLY ADAPTED THEREFOR
    • G03F7/00—Photomechanical, e.g. photolithographic, production of textured or patterned surfaces, e.g. printing surfaces; Materials therefor, e.g. comprising photoresists; Apparatus specially adapted therefor
    • G03F7/0037—Production of three-dimensional images
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C64/00—Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
    • B29C64/10—Processes of additive manufacturing
    • B29C64/106—Processes of additive manufacturing using only liquids or viscous materials, e.g. depositing a continuous bead of viscous material
    • B29C64/112—Processes of additive manufacturing using only liquids or viscous materials, e.g. depositing a continuous bead of viscous material using individual droplets, e.g. from jetting heads
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C64/00—Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
    • B29C64/10—Processes of additive manufacturing
    • B29C64/106—Processes of additive manufacturing using only liquids or viscous materials, e.g. depositing a continuous bead of viscous material
    • B29C64/124—Processes of additive manufacturing using only liquids or viscous materials, e.g. depositing a continuous bead of viscous material using layers of liquid which are selectively solidified
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/0068—General culture methods using substrates
    • G—PHYSICS
    • G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
    • G03F—PHOTOMECHANICAL PRODUCTION OF TEXTURED OR PATTERNED SURFACES, e.g. FOR PRINTING, FOR PROCESSING OF SEMICONDUCTOR DEVICES; MATERIALS THEREFOR; ORIGINALS THEREFOR; APPARATUS SPECIALLY ADAPTED THEREFOR
    • G03F7/00—Photomechanical, e.g. photolithographic, production of textured or patterned surfaces, e.g. printing surfaces; Materials therefor, e.g. comprising photoresists; Apparatus specially adapted therefor
    • G03F7/004—Photosensitive materials
    • G03F7/027—Non-macromolecular photopolymerisable compounds having carbon-to-carbon double bonds, e.g. ethylenic compounds
    • G—PHYSICS
    • G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
    • G03F—PHOTOMECHANICAL PRODUCTION OF TEXTURED OR PATTERNED SURFACES, e.g. FOR PRINTING, FOR PROCESSING OF SEMICONDUCTOR DEVICES; MATERIALS THEREFOR; ORIGINALS THEREFOR; APPARATUS SPECIALLY ADAPTED THEREFOR
    • G03F7/00—Photomechanical, e.g. photolithographic, production of textured or patterned surfaces, e.g. printing surfaces; Materials therefor, e.g. comprising photoresists; Apparatus specially adapted therefor
    • G03F7/20—Exposure; Apparatus therefor
    • G03F7/2051—Exposure without an original mask, e.g. using a programmed deflection of a point source, by scanning, by drawing with a light beam, using an addressed light or corpuscular source
    • G03F7/2053—Exposure without an original mask, e.g. using a programmed deflection of a point source, by scanning, by drawing with a light beam, using an addressed light or corpuscular source using a laser
    • G—PHYSICS
    • G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
    • G03F—PHOTOMECHANICAL PRODUCTION OF TEXTURED OR PATTERNED SURFACES, e.g. FOR PRINTING, FOR PROCESSING OF SEMICONDUCTOR DEVICES; MATERIALS THEREFOR; ORIGINALS THEREFOR; APPARATUS SPECIALLY ADAPTED THEREFOR
    • G03F7/00—Photomechanical, e.g. photolithographic, production of textured or patterned surfaces, e.g. printing surfaces; Materials therefor, e.g. comprising photoresists; Apparatus specially adapted therefor
    • G03F7/26—Processing photosensitive materials; Apparatus therefor
    • G03F7/40—Treatment after imagewise removal, e.g. baking
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y80/00—Products made by additive manufacturing
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2533/00—Supports or coatings for cell culture, characterised by material
    • C12N2533/30—Synthetic polymers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2533/00—Supports or coatings for cell culture, characterised by material
    • C12N2533/50—Proteins

Definitions

  • the present invention relates to a method for producing a two- or three-dimensional structure, which is preferably biocompatible and biofunctionalized, the thus prepared two- or three-dimensional structure and an apparatus for producing this two- or three-dimensional structure.
  • the oxygen supply of the cells in a tissue composite can be effected by diffusion over a distance of at least 150 ⁇ m to 200 ⁇ m (C.K. Colton, Cell Transplantation, 1995, 4). This means that every cubic millimeter of tissue must be supplied by at least one capillary which carries oxygenated and nutrient-rich blood. Tissue supply with blood vessels is now considered one of the central, unsolved problems on the way to the breeding of functional, three-dimensional tissue.
  • Plastic vascular prostheses PET polyethylene terephthalate, Dacron®
  • PTFE polytetrafluoroethylene
  • PET polyethylene terephthalate
  • PTFE polytetrafluoroethylene
  • ECM extracellular matrix proteins
  • vascular replacement L. Buttafoco et al., Biomaterials, 2006, 27 (11), 2380-2389.
  • muscle cells are cultured on biodegradable polymer tubes which, as they grow, secrete an ECM mesh of proteins that gradually build up a vascular tube.
  • the vessel tube After removal of the polymer tube and chemical detachment of the cells, the vessel tube remains of proteins, which due to its freedom from cells does not cause any immune reactions and is also storable in buffer solution (S. Dahl et al., Science Translational Medicine, 3 (68), 68ra9). Both are time-consuming and costly because they are based on the recovery of biological materials.
  • a laser-based build-up method according to the stereolithography method, abbreviated to SL method, is known, in which a planar surface applied in a working plane, light-curing plastic is cured by a laser location-selective. The procedure is carried out in a bath which is filled with a liquid or pasty base monomer of the photosensitive plastic.
  • the structural regions in the working plane which form locally selectively due to the initiation with laser light are reduced by the amount of a layer thickness move into the bath, so that again a plastic layer can form over the solidified structural areas within the working plane.
  • the laser beam is controlled by moving mirrors along the working plane so that the exposed plastic layer areas solidify and unite integrally with the underlying solidified structures.
  • DE 100 24 618 A1 discloses such a stereolithographic process for producing three-dimensional objects, in which liquid to gelatinous silicone rubbers are irradiated with an IR laser.
  • US 2009/0224438 describes the layered processing of 3D objects by means of SL methods with UV or Vis light photocrosslinking materials.
  • SL processes have the disadvantage that only a single photo-crosslinkable material can be used for the construction of a three-dimensional structure.
  • the structure resolution that is, the structure size dimensioning
  • limits are set with regard to the elastic structural properties, especially since the plastic materials which can be processed by the SL process and which are known in the prior art have dimensionally stable and thus low elastic properties.
  • Another variant of the method for the production of one-piece structures or components by means of generative manufacturing processes is the so-called 3D printing technology (for example US Pat. No. 6,658,314 B1), which makes it possible to produce three-dimensional parts with almost unlimited freedom of geometry using a plurality of different materials, so that, for example, elastics can be set locally selective. Due to the one-piece production of the structures can be dispensed with a subsequent joining of individual parts for the production of complex structures.
  • the photocrosslinkable materials used in the abovementioned processes have the disadvantage that they can not be used universally, ie in any process for producing a two- or three-dimensional structure . You need to each adapted to the requirements of a particular process, so that the use in each other's processes for the production of two- or three-dimensional structures is not possible.
  • the technical problem underlying the present invention is therefore to overcome the aforementioned disadvantages, in particular to provide methods for producing two- or three-dimensional structures which overcome the aforementioned disadvantages.
  • photocrosslinkable materials these materials being universally usable in different electromagnetic radiation for photocrosslinking of the materials - in some cases known per se - methods for producing a two-dimensional or three-dimensional structure, without a specific - See customization of these photocrosslinkable materials must be made to meet the requirements of each specific procedure.
  • the technical problem is solved by a method for producing a two- or three-dimensional structure on a substrate comprising at least the following steps, in particular the following sequence of processes, preferably consisting of these steps: a) applying at least one photocrosslinkable material to the substrate and b) fixing the at least one photocrosslinkable material applied in step a) by electromagnetic radiation, wherein the at least one photocrosslinkable material comprises the following components: i) at least one polymeric crosslinker component having at least two photocrosslinkable groups selected from the group consisting from acrylate, methacrylate, acrylamide, methacrylamide, urethane acrylate, urethane methacrylate, urea acrylate and urea methacrylate and ii) at least one photoinitiator component.
  • the process sequence of steps a) and b) produces at least one layer of the two-dimensional or three-dimensional structure, wherein first in a step a) the photocrosslinkable material comprising at least one polymeric crosslinker component and at least one photoinitiator component, applied to the substrate, which in particular has a supporting and / or modeling effect during the production of the two- or three-dimensional structure, and wherein in a step b) the applied photocrosslinkable material is fixed by electromagnetic radiation.
  • step b) at least part, in particular substantially all, preferably all of the photocrosslinkable groups of the photocrosslinkable material react with one another, whereby a photocrosslinked material is obtained.
  • step b) takes place in such a way that the photo-initiator component present in the photocrosslinkable material, in particular for cleavage, is excited by the electromagnetic radiation in order to produce a photo-initiated potential.
  • polymerization reaction of the photocrosslinkable groups of the photocrosslinkable material By means of this controlled chain reaction, at least part, preferably substantially all, preferably all of the photocrosslinkable groups lying in the electromagnetically irradiated areas are reacted.
  • the sequence of process steps a) and b) leads to the formation of a fixed layer of the applied material.
  • the inventively preferred repeated sequence of process steps a) and b) leads to the formation of a corresponding number of fixed layers.
  • the photocrosslinkable material is fixed by the electromagnetic radiation within a layer applied in step a) in all three spatial directions x, y and z, ie three-dimensional, areal or location-selective, in particular location-selective.
  • a two- or three-dimensional substructure within a layer is produced by a sequence of steps of steps a) and b).
  • step a) takes place either areally or location-selective, wherein the subsequent fixing in step b) of the photocrosslinkable material to a photo-crosslinked material is effected by an electromagnetic radiation, which in a preferred embodiment in particular to those contained in the photocrosslinkable material Photoinitiator component is tuned and also ensures a site-selective or areal irradiation.
  • a layer of the two- or three-dimensional structure is built up. According to the invention, it is preferred to repeat two or more or several repetitions of process sequence a) and b) two or more. or to provide many layers.
  • a creation of a further layer which connects covalently with the already photocrosslinked material takes place.
  • photocrosslinkable materials combine with different photosensitivities.
  • the two- or three-dimensional structure produced according to the invention preferably has desired polymer properties for, for example, implants.
  • the photocrosslinkable materials used according to the invention are distinguished in particular by a suitable surface tension and viscosity, in particular by a viscosity of less than 200 mPas, in particular less than 80 mPas, particularly preferably less than 40 mPas.
  • This viscosity can be achieved in particular by solvents, in particular by a reactive diluent, with a proportion of less than 51%.
  • the surface tension of the photocrosslinkable material is less than 80 mN / m, in particular less than 70 mN / m, in particular less than 35 mN / m.
  • the photocrosslinkable materials preferably have the, for the methods for producing a two-dimensional or three-dimensional structure, in particular for SL methods, 3D printing methods and MPP methods, required, especially high, light transparency for the curing wavelength of the electromagnetic radiation and a sufficient cure rate.
  • the light transparency is preferably in the VIS-NIR range or UV range.
  • the electromagnetic radiation is additionally absorbed by the photocrosslinkable materials.
  • the photocrosslinkable material has sufficient degrees of crosslinking with regard to its photo-crosslinkability, can be selectively fixed by the electromagnetic radiation and preferably reacts selectively to a preferably provided areal and spatially-resolved crosslinking. Furthermore, the photocrosslinkable material satisfies in particular the requirements of 3D printing processes, for example inkjet printing, with regard to the viscosity to be maintained, the flow behavior and the pressure stability.
  • the present invention employs at least one photoinitiator component as a component of the photocrosslinkable material.
  • the photoinitiator component allows the most effective and selective fixation of the photocrosslinkable material, in particular in combination with a sufficiently fast curing rate of the photocrosslinkable material.
  • the photoinitiator component used according to the invention has a high photon absorption cross section, in particular a high two-photon absorption cross section in the VIS-NIR, and preferably a high quantum yield.
  • planar in particular a flat application of a photocrosslinkable material or a planar fixing of an applied photocrosslinkable material, means that the application of the material or the fixing radiation takes place uniformly over the entire material layer to be coated or fixed Accordingly, a two-dimensional application of a material or a surface action of the radiation can lead to the formation of three-dimensionally formed or fixed layers, in particular due to the extensive application of material or surface exposure of the radiation, the photocrosslinkable material is uniformly applied or fixed.
  • the term "site-selective”, in particular a spatially selective application of a photocrosslinkable material or a location-selective fixing of an applied photocrosslinkable material, means that the application of the material or the fixing radiation does not take place uniformly over the entire applied material layer.
  • polymeric crosslinker component having at least two terminal photocrosslinkable groups is to be understood as meaning an unbranched or at least mono-branched polymer or oligomer to which the at least two photocrosslinkable groups are covalently bonded in such a way that they are immobilized by the electromagnetic radiation in step
  • the polymeric crosslinker component has functional groups to which the photocrosslinkable groups are covalently bonded, Preferably, this covalent bond between the polymeric crosslinker component and the photocrosslinkable groups is via one Ester or amide bond instead.
  • polymeric crosslinker component refers to the component to which the photocrosslinkable groups are covalently bonded.
  • two-dimensional structure in a three-dimensional space with the spatial axes xyz is understood to mean a structure with edge lengths x'-y'-z 'along the spatial axes, where the length of the shortest edge of x' and y 'is one the edges x 'and y' is significantly larger than the edge length z ', preferably by a factor of 5, preferably 10, preferably 20, preferably 30, preferably 40, preferably 50, preferably 100, preferably 1000, preferably 10000. Accordingly, the term "two-dimensional structure” does not mean that there is no spatial expansion in the direction of the third dimension.
  • the two-dimensional structure in the direction of the third dimension preferably has 1 to 50 layers, in particular 1 to 40 layers, preferably 1 to 20 layers, preferably 1 to 10 layers and particularly preferably 5 to 10 layers.
  • layers in particular 1 to 40 layers, preferably 1 to 20 layers, preferably 1 to 10 layers and particularly preferably 5 to 10 layers.
  • membranes, nonwovens, skin-like implants and nets are understood as two-dimensional structures.
  • short-chain crosslinker component having at least three terminal photocrosslinkable groups is to be understood as meaning a branched multiply functionalized molecule which preferably has a maximum chain length per branch of 10, preferably 8, preferably 6.
  • the short-chain crosslinker component has functional groups on which the photochemical crosslinkable groups are covalently bonded. This covalent bond between the short-chain crosslinker component and the photocrosslinkable groups preferably takes place via an ester or amide bond.
  • the term "short-chain crosslinker component" refers to the component to which the photocrosslinkable groups are covalently bonded.
  • low-viscosity modifier component is understood to mean a component which preferably has a molecular weight of less than 1000 g / mol and adapts the viscosity of the photocrosslinkable material such that a viscosity range is ensured which is suitable for the universal application of the photocrosslinkable materials in the US Pat Process for the production of two- or three-dimensional structures guaranteed.
  • the low-viscosity modifier component and / or the polymeric and / or short-chain crosslinker component preferably have further non-photocrosslinkable functional groups which can not covalently, in particular not at all, bind to the photocrosslinkable groups and thus for coupling reactions, in particular with biofunctional ones Components are available.
  • These non-photocrosslinkable functional groups are preferably selected from the group consisting of hydroxyl, cyanate, isocyanate, amino, imino, alkene, alkyne, carboxy group, preferably carboxy group.
  • working plane is understood to mean the plane in which the fixation carried out in step b) is effected by the electromagnetic radiation. ⁇ br/> Preferably, this plane runs planar, essentially planar, curved or substantially curved.
  • process sequence of steps a) and b) is understood to mean that the photocrosslinkable material is applied in a step a), either in a spatially selective or planar manner, and in a step b) the photocrosslinkable material applied in step a) is fixed location-selectively, wherein preferably when step a) is location-selective, step b) surface or when step a) takes place areally, step b) is location-selective.
  • photocrosslinkable materials with different photosensitivity is to be understood as meaning that the photocrosslinkable materials have a photoinitiator component with different photosensitivity.
  • the two-dimensional or three-dimensional structure is classified as "biocompatible" if at least 20%, preferably at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, of the viability of a comparison cell culture is reached after 24 hours in a cell culture to be investigated
  • the cell culture to be examined has a culture medium which is obtained by subjecting the photocrosslinked material, which is to be examined for its biocompatibility, to a cell culture
  • the viability (WST value) is preferably determined by means of a WST-1 proliferation assay
  • different cell types are used, preferably endothelial cells, preferably chondrocytes.
  • the electromagnetic radiation used in step b) depends in a preferred embodiment according to the requirements of the performed in step b) fixing.
  • the electromagnetic radiation in step b) must be able to selectively excite the photoinitiators used in the photocrosslinkable material so as to ensure in a targeted manner the fixation of the photocrosslinkable material.
  • the planar fixation preferably takes place with the aid of UV light, with the spectral range preferably being adapted to the requirements of the method carried out or to the photoinitiator component. In particular, the spectral range is from 250 to 500 nm.
  • the source of the UV light is preferably UV emitters, in particular with limited spectral range, or LEDs (light-emitting diodes).
  • the polymeric crosslinker component has two, three, four, five or more than 50, preferably more than 70, preferably more than 100, photocrosslinkable groups.
  • the polymeric crosslinker component has two or three photo-crosslinkable groups.
  • the photocrosslinkable material comprises at least 2, at least 3, at least 4 or at least 5 different polymeric Vemet zer components with at least two photocrosslinkable groups.
  • the polymeric crosslinker component having at least two photocrosslinkable groups has a molecular weight of 300 to 3000 g / mol.
  • the polymeric crosslinker component having at least two photocrosslinkable groups is an alpha, omega-hydroxy oligomer, an alpha, omega-amino oligomer and / or an alpha-hydroxy-omega-amino-oligomer.
  • the polymeric crosslinker component is selected from the group consisting of polyethylene glycol (PEG), polypropylene glycol (PPG), siloxanes, polytetrahydrofuran (PTHF), bisphenol A ethoxylate (BPA (EO)), Co Block polyethers thereof, biopolymers and modified biopolymers.
  • PEG polyethylene glycol
  • PPG polypropylene glycol
  • siloxanes siloxanes
  • PTHF polytetrahydrofuran
  • BPA (EO) bisphenol A ethoxylate
  • Co Block polyethers thereof biopolymers and modified biopolymers.
  • the polymeric crosslinker component is selected from the group consisting of polyethylene glycol (PEG), polypropylene glycol (PPG), polytetrahydrofuran (PTHF), bisphenol A ethoxylate (BPA (EO)), co-block Polyethers thereof, biopolymers and modified biopolymers.
  • PEG polyethylene glycol
  • PPG polypropylene glycol
  • PTHF polytetrahydrofuran
  • BPA bisphenol A ethoxylate
  • co-block Polyethers thereof biopolymers and modified biopolymers.
  • the polymeric crosslinker component having at least two photocrosslinkable groups selected from the group consisting of PTHF (1400) diacrylate, PTHF (2000) diacrylate, PTHF (2900) diacrylate, PPG (2000) Diacrylate, PPG (2300) diurethane methacrylate and PTHF (1600) diurethane methacrylate.
  • the brackets Numbers indicate the average molecular weight of the polymeric crosslinker component.
  • the biopolymer also called biological macromolecule, is selected from the group consisting of proteins, polysaccharides, glucosaminoglycans and derivatives thereof.
  • the protein is selected from the group consisting of albumin, collagens, gelatin and fibronectin.
  • a negative-charge modified biopolymer in particular heparin sulfate, is used as the photocrosslinkable material. These negative charges preferably bind growth factors, analogs, fragments and / or derivatives thereof ionically, in particular temporarily.
  • the growth factor is selected from the group consisting of VEGF (Vascular Endothelial Growth Factor), FGF (Fibroblast Growth Factor), PDGF (Platelet Derived Growth Factor), Pleitrophin, PIGF (Placenta Growth Factor), HGF / SF (Hepatocyte Growth Factor / Scatter Factor) and Midkine.
  • the polysaccharide is selected from the group consisting of cellulose, starch and glycogen.
  • the glucosaminoglycan is selected from the group consisting of hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparin sulfate and heparin.
  • part of the photo-crosslinkable groups in the at least one photocrosslinkable material in step b) is not reacted, in particular 1 to 60%, in particular 10 to 50%, in particular 20 to 40% of the photocrosslinkable groups used.
  • the unreacted or unfixed photocrosslinkable groups of the photocrosslinked structure are available in particular for further surface functionalization and / or biofunctionalization.
  • the photocrosslinkable or photocrosslinked material e.g. B. also used as a polymeric crosslinker component modified or unmodified biopolymer functionalized with at least one biofunktio- nellen component.
  • the at least one biofunctional component is linked directly or indirectly to the photocrosslinkable or photocrosslinked material.
  • the present invention provides that the photocrosslinkable material is functionalized prior to fixation with a biofunctional component, in particular prior to application.
  • the at least one biofunctional component is introduced after fixing the photocrosslinkable material, that is covalently or non-covalently bound to the surface of the photocrosslinked material.
  • the unreacted, photocrosslinkable groups are functionalized with at least one biofunctional component.
  • the non-photocrosslinkable functional groups of the low-viscosity modifier component and / or short-chain and / or polymeric crosslinker component are functionalized with at least one biofunctional component.
  • this biofunctionalization takes place via an amide bond, with carbodiimide preferably being used as the reaction mediator for its formation.
  • the biofunctionalization of the two- or three-dimensional structure takes place by targeted incorporation of biofunctional components into the two- or three-dimensional structure, in particular by biofunctionalizing the photocrosslinkable material before fixing the photocrosslinkable material in step b) or on the unreacted double bonds and / or the non-photocrosslinkable functional groups of the photocrosslinked material.
  • the material to be biofunctionalized that is to say the photocrosslinked or photocrosslinkable material, itself is a biopolymer or a modified polymer Biopolymer is or includes.
  • the biofunctionalizing material may in particular be the polymeric crosslinker component or the short chain crosslinker component.
  • Biofunctionalization is particularly preferred in the use of the two- or three-dimensional structure in biological or medical use, e.g. B. especially as a vein substitute material, eg.
  • a vein substitute material e.g.
  • the antithromogeneous properties of the two- or three-dimensional structure are preferably achieved in particular via the sequential attachment of modified heparin, in particular heparin sulfate.
  • the biofunctional component used for biofunctionalization of the photocrosslinked material is selected from the group consisting of proteins such as glycoproteins, growth factors or antibodies, peptide sequences, polysaccharides, glycosaminoglycans, nucleic acids, aptamers and derivatives thereof as well as combinations thereof.
  • biopolymers or modified biopolymers characterized as biofunctional component can also be used as polymeric crosslinker components of the photocrosslinkable material.
  • polymeric crosslinker components of the photocrosslinkable material listed as biopolymers or modified biopolymers can also be used as biofunctional components for the biofunctionalization of the photocrosslinked or photocrosslinkable material, in particular the polymeric or short-chain crosslinking component, especially when the polymeric crosslinker component is designed as a biopolymer or modified biopolymer.
  • step a) acrylated gelatin is used as the polymeric crosslinker component having at least two photocrosslinkable groups.
  • the photocrosslinked structure according to step b) thereby contains attachment sites for integrin as receptor for binding of cells.
  • biofunctionalization occurs after preparing a photocrosslinked structure and removing the substrate and cytotoxic agents such as the photoinitiator component and / or the support structure by post-treatment.
  • the photocrosslinkable or photocrosslinked, preferably photocrosslinked, material is functionalized, preferably via a Michael addition, with organic primary amines, gelatin and / or thioheparin sulfate.
  • thiol-modified biopolymers in particular proteins such as collagen, gelatin and fibronectin or polysaccharides such as cellulose, starch, glycogen, hyaluronic acid, chondroitin sulfate, heparin sulfate and heparin, in particular heparin sulfate, to the unreacted double bonds of the two- or three-dimensional structure, in particular to the surface of this structure, covalently bound via a thiol-En-Michael addition.
  • This biofunctional tion is preferably carried out after each process sequence of steps a) and b).
  • the Michael addition and the process sequence of steps a) and b) are carried out alternately.
  • not all thiol groups of the modified biopolymer are reacted via the thiol-en-Michael addition.
  • these unreacted thiol groups are preferred at least partially with preferably acrylate-modified biopolymers, in particular proteins such as collagen, gelatin and fibronectin or polysaccharides such as cellulose, starch, glycogen, hyaluronic acid, chondroitin sulfate, heparin sulfate and heparin, in particular heparin sulfate , reacted via a thiol-en-Michael addition.
  • proteins such as collagen, gelatin and fibronectin
  • polysaccharides such as cellulose, starch, glycogen, hyaluronic acid, chondroitin sulfate, heparin sulfate and heparin, in particular heparin sulfate
  • the preferably alternating reaction of the photocrosslinked structure produced with thiol-modified biopolymers and acrylate-modified biopolymers is preferably repeated until the surface of the two-dimensional or three-dimensional structure contains the modified biopolymer in the desired proportion or degree of coverage.
  • the protein used for the biofunctional component is a structural protein such as collagen and / or a denatured protein such as gelatin.
  • the glycosaminoglycan used for the biofunctional component is heparin, heparin sulfate, chondroitin sulfate and / or keratan sulfate.
  • biofunctional components for example adhesion anchors, in particular Cys-RGD (cysteine-arginine-glycine aspartate), are covalently, in particular via a thiol-ene -Michael addition or by oxidative formation of disulfide bridges, bound, preferably for stable adhesion of cells to the surface of the two- or three-dimensional structure, preferably for complete endotheliarization.
  • adhesion anchors in particular Cys-RGD (cysteine-arginine-glycine aspartate)
  • Cys-RGD cyste-arginine-glycine aspartate
  • disulfide bridges bound, preferably for stable adhesion of cells to the surface of the two- or three-dimensional structure, preferably for complete endotheliarization.
  • the biofunctional component is indirectly linked to the photocrosslinkable or photocrosslinked material via nanoparticles.
  • the nanoparticles have molecule-specific recognition sites.
  • the biofunctional component is covalently or non-covalently bound to the nanoparticles.
  • the nanoparticles have the biofunctional component in their interior.
  • the nanoparticles have cavities in their interior, the biofunctional component being present in the cavities.
  • the nanoparticles comprise a polymeric matrix material, wherein the biofunctional component is mixed with the polymeric matrix material and optionally ionically bound.
  • the encapsulated biofunctional component is released by dissolving the nanoparticle in a solvent, preferably water.
  • the nanoparticle consists of covalently or noncovalently crosslinked biofunctional components.
  • the nanoparticles have, on their surface, molecule-specific recognition sites to which, in a preferred embodiment of the present invention, the biofunctional component is covalently or noncovalently bound to nanoparticles.
  • the at least one biofunctional component has at least one functional group with which the biofunctional component is associated with the nanoparticles, in particular with the molecule-specific recognition sites of the nanoparticles.
  • the binding of the biofunctional component with the at least one functional group to the molecule-specific recognition points of the nanoparticles is carried out on the first functional group-specific recognition sites of the nanoparticles having the first functional group-binding, complementary second functional groups biofunctional components are brought into contact such that covalent and / or non-covalent bonds between the functional groups of the molecule-specific recognition sites and the biofunctional components take place.
  • the first functional groups and the complementary second functional groups which bind the first functional groups are selected from the group consisting of active ester, alkyl ketone group, aldehyde group, amino group, carboxy group, epoxy group, maleimido group, hydrate group, hydrazide group , Thiol group, thioester group, oligohistidine group, Strep tag I, Strep tag II, desthiobiotin, biotin, chitin, chitin derivatives, chitin binding domain, metal chelate complex, streptavidin, streptactin, avidin and neutravidin.
  • a biocompatible structure is prepared, wherein the polymeric crosslinker component in an amount of 5 to 80% by mass, in particular 5 to 30% by mass, and the at least one photoinitiator component in an amount of 0 , 2 to 4 mass%, preferably 0.5 to 1 mass%, preferably less than 0.5 mass% is present.
  • the photocrosslinkable material additionally comprises at least one short-chain crosslinker component having at least three photocrosslinkable groups selected from the group consisting of acrylate, methacrylate, acrylamide, methacrylamide, urethane acrylate, urethane methacrylate, urea acrylate and urea methacrylate.
  • the short chain crosslinker component is selected from the group consisting of short chain polyfunctional alcohols and short chain polyfunctional amines.
  • the short-chain crosslinker component is selected from the group consisting of trimethylolpropane, pentaerythritol, trimethylolpropane propoxylate, glycerol propoxylate, trimethylolpropane and di (trimethylolpropane).
  • the short-chain crosslinker component having at least three photocrosslinkable groups is selected from the group consisting of trimethylolpropane triacrylate, pentaerythritol triacrylate, trimethylolpropane propoxylate triacrylate, glycerol propoxylate triacrylate, trimethylolpropane trimethacrylate, di (trimethylolpropane) tetraacrylate and pentaerythritol tetraacrylate.
  • the photocrosslinkable material additionally comprises at least one low-viscosity modifier component having a photocrosslinkable group selected from the group consisting of acrylate, methacrylate, acrylamide, methacrylamide, urethane acrylate, urethane methacrylate, urea acrylate and urea methacrylate.
  • the low-viscosity modifier component is lauryl acrylate and / or isobornyl acrylate.
  • the photocrosslinkable material additionally comprises at least one diluent component.
  • the diluent component is an aqueous or organic solvent which preferably has a high vapor pressure.
  • the high vapor pressure of the aqueous or organic solvent serves for the partial or complete, rapid volatilization prior to the curing of the photocrosslinked in step b) material.
  • the photoinitiator component is selected from the group consisting of alpha-hydroxy ketones, alpha-morpholino ketones, phosphine oxides, camphorquinones, ⁇ , ⁇ , ⁇ ', ⁇ '-substituted benzidines, tri-aryl substituted amines and Diynone.
  • the photoinitiator component is selected from the group consisting of 1-hydroxycyclohexylphenyl ketone, 4- (2-hydroxyethoxy) phenyl- (2-hydroxy-2-propyl) ketone, phenyl bis (2,4,6-trimethylbenzoyl ) -phosphine oxide, 2-hydroxy-2-methyl-1-phenylpropan-1-one, 2-methyl-1- [4- (methylthio) phenyl] -2-morpholinopropan-1-one, N 4 , N 4 bis (3-methoxyphenyl) -N 4 , N 4 -diphenyl-4,4'-diaminobiphenyl and 1, 5-diphenyl-1,4-diyn-3-one.
  • the photocrosslinkable materials used for site-selective fixing comprise at least one photoinitiator component selected from the group consisting of 1-hydroxycyclohexyl phenyl ketone, 4- (2-hydroxyethoxy) phenyl (2-hydroxy-2-propyl) ketone and N 4 , N-bis (3-methoxyphenyl) -N, N 4 -diphenyl-4,4'-diaminobiphenyl.
  • the photocrosslinkable material comprises a photoinitiator component selected from the group consisting of 1-hydroxycyclohexyl phenyl ketone, 4- (2-hydroxyethoxy) phenyl- (2-hydroxy-2-propyl) ketone , Phenylbis (2,4,6-trimethylbenzoyl) -phosphine oxide, 2-methyl-1- [4- (methylthio) phenyl] -2-morpholinopropan-1-one, N 4 , N 4 -bis (3-methoxyphenyl) - N 4 , N 4 -diphenyl-4,4'-diaminobiphenyl and 1,5-diphenyl-1,4-diyn-3-one.
  • photoinitiator Components are particularly preferably usable for producing a biocompatible two- or three-dimensional structure.
  • the photocrosslinkable material additionally comprises at least one stabilizer component selected from the group consisting of hydroquinones and monomethyl ether hydroquinones, preferably in an amount of less than 500 ppm, preferably less than 200 ppm, preferably less than 100 ppm (based on the amount of the components present in the photocrosslinkable material).
  • a stabilizer component preferably prevents spontaneous or thermally uncontrolled polymerizations of the photocrosslinkable material.
  • the photocrosslinkable material comprises at least one polymeric crosslinker component having at least two photocrosslinkable groups, a short-chain crosslinker component having at least three photocrosslinkable groups, a low-viscosity modifier component having a photocrosslinkable group, at least one photoinitiator component, a component for biofunctionalization and an aqueous or organic solvent.
  • the photocrosslinkable material additionally contains an absorber component, which, in particular for SL processes, increases the structure resolution in the beam direction of the electromagnetic radiation.
  • the application of the at least one photocrosslinkable material takes place in step a) the substrate in a location-selective manner and the fixing of the at least one material photocrosslinkable in step a) in step b) by electromagnetic radiation.
  • the application of the at least one photocrosslinkable material to the substrate takes place in a planar manner and the fixing of the at least one photocrosslinkable material applied in step a) in step b) by electromagnetic Radiation site-selective.
  • the application of the at least one photocrosslinkable material to the substrate takes place in a planar manner and the fixing of the at least one photocrosslinkable applied in step a) is carried out in step b) Material by electromagnetic radiation surface.
  • step a) the application of the at least one photocrosslinkable material to the substrate is location-selective and the fixing of the at least one photocrosslinkable applied in step a) is carried out in step b) Materials are site selective by electromagnetic radiation.
  • the process sequence of steps a) and b) is carried out at least twice, preferably at least 500 times, preferably at least 1000 times, preferably 2 to 600 times, in particular 400 to 600 times, preferably 500 times.
  • the method is carried out such that one, two, three or all four of the aforementioned process sequences are carried out alone or in combination with each of the different process sequences being carried out once, several times or many times.
  • At least one first photocrosslinkable material is selectively applied to the substrate and fixed in a step b) by electromagnetic radiation, in particular for producing a centimeter or millimeter, So macroscopic structure, and then in a second process sequence in a step a) at least a second photocrosslinkable material applied to the substrate and in a step b) this location-selectively fixed by electromagnetic radiation, in particular for producing a micro- or submicron-sized substructure.
  • the first process sequence of steps a) and b) is at least twice, preferably at least 500 times, preferably at least 1000 times, preferably 2 to 600 times, in particular 400 to 600 times, in particular 500 times and the second process sequence of steps a) and b) additionally at least 2 times, preferably min. at least 500 times, preferably at least 1000 times, preferably 2 to 600 times, in particular 400 to 600 times, in particular 500 times.
  • the first process sequence of steps a) and b) is carried out alternately with the second process sequence of steps a) and b).
  • a photocrosslinkable material is used in a first process sequence of steps a) and b), which differs from a photocrosslinkable material used in a second process sequence of steps a) and b), in particular in terms of their photosensitivity.
  • At least two different photocrosslinkable materials with different photosensitivities are used in the process sequence of steps a) and b).
  • at least one photocrosslinkable material and at least one non-photocrosslinkable support material are used in the process sequence of steps a) and b).
  • the non-photocrosslinkable support material forms a support structure.
  • a rigid or flexible substrate is used as substrate, in particular the substrate may be made of a plastic material.
  • the substrate may be a plastic film, plastic film, membrane, glass, metal, semi-metal, non-woven or paper, preferably of biocompatible, in particular biodegradable material.
  • the substrate is separated from the resulting two- or three-dimensional structure, in particular by chemical, physical or biological degradation, following step b), preferably after completion of a repeated execution of the process sequences a) and b).
  • the substrate remains after step b), preferably after completion of a repeated execution of the process sequences a) and b), part of the fabricated structure, thus becoming an integral part of the two- or three-dimensional structure.
  • biocompatibility is provided by special washing protocols.
  • it is washed with polar and / or non-polar organic solvents and aqueous buffer solutions.
  • it is washed daily for 3 days with 3 ml of 70% ethanol (based on a material surface of 7 cm 2 ).
  • the problem of the invention is further solved by a two- or three-dimensional structure preparable according to one of the inventive method.
  • the two- or three-dimensional structure has an modulus of elasticity (elastic modulus) of from 0.1 to 100 MPa, preferably from 1 to 40 MPa, preferably from 1 to 20 MPa, preferably from 0.5 to 10 MPa ,
  • the two- or three-dimensional structure has a swellability in water of 1 to 700%, preferably 300 to 700%, preferably 1 to 500%, preferably 1 to 100%, preferably 1 to 10%, in particular 0 , 5 to 5% up.
  • the two- or three-dimensional structure has a tensile strength (sigma) of 0.01 to 10 MPa, preferably 0.1 to 1 MPa.
  • the cells cultured on the non-biofunctionalized two- or three-dimensional structure (depending on the application of different cell types) have a confluence of at least 10%, preferably at least 50%, preferably at least 80% after 48 hours.
  • the cells cultured on the biofunctionalized two- or three-dimensional structure (depending on the application of different cell types) have a confluence of at least 50%, preferably at least 60%, preferably at least 80%, preferably at least 90% after 48 hours. on.
  • the two- or three-dimensional structure is a matrix for colonization with cells for producing an in vitro or in vivo tissue, an organ part or organ part equivalent, an organ or organ equivalent, a transplant, an implant, a vascular, a vascular system, a hollow organ or a part of a hollow organ, a cell culture substrate, porous or non-porous transport systems, porous or non-porous tube systems, porous or non-porous tubes, a membrane, a diagnostic system or a surgical device, in particular an endoscope, or a part thereof.
  • the two- or three-dimensional structure is an in vitro or in vivo tissue, an organ part or organ part equivalent, an organ or organ equivalent, a transplant, an implant, a vessel, a vascular system, a hollow organ or a part of a hollow organ, a cell culture substrate, porous or non-porous transport systems, porous or non-porous porous tube systems, porous or non-porous tubes, a membrane, a diagnostic system or a surgical device, in particular an endoscope, or part thereof.
  • the vessel or vasculature is a blood vessel such as an artery, vein or capillary, a lymphatic vessel such as lymphatic capillaries, collectors, lymphatic stems, a salivary or tear duct, or another gangue for glandular secretions such as bile, milk or semen ,
  • the hollow organ is a gullet, a gastrointestinal tract, a gallbladder, a trachea, a heart, an oviduct, a vas deferens, a ureter, a urinary bladder or a urethra.
  • the two- or three-dimensional structure according to the invention is preferably suitable for use as a vascular system.
  • the two- or three-dimensional structure is therefore characterized by their biocompatibility, their complete curing as possible to avoid toxic monomeric constituents, the presence of the lowest possible photoinitiator quantities with little or no toxicity, the realization of sufficient elastic properties in the cured material, a sufficient mechanical and biological Long-term stability and a biofunctional or biofunctionalizable surface.
  • a device for the layer-by-layer production of 3D structures with a printhead arrangement which can be positioned in a controlled manner relative to the working plane and is connected to at least two reservoir containers in which liquid to pasty photocrosslinkable materials, each with different photosensitivities, are stored , which can be applied selectively in each case via the print head arrangement in the region of the working plane, and with a radiation source arrangement which emits electromagnetic radiation as a function of the photosensitivity of the photocrosslinkable material applied to the work plane in a planar manner, characterized in that the radiation source arrangement comprises at least one laser light source , whose laser beam by means of optical beam deflection and focusing means in a region of a plane on the working plane by means of the printhead assembly ausbri nentable photocrosslinkable material layer is focused and initiated in the focus area within the photocrosslinkable material layer two photon or Mehrphotonrake that lead to the site-selective solidification of the photocrosslinkable material.
  • a method for the layered production of 3D structures with a printhead assembly is provided, is applied from the liquid to pasty photocrosslinkable material, in particular the present invention, each with different photosensitivities dosed on a work surface and each with a electromagnetic radiation irradiated to the photosensitivity of the photocrosslinkable material applied to the working plane, in particular of the present invention, is illuminated in a planar manner, whereby the applied photocrosslinkable material solidified and in order to form a macroscopic structure of the printhead assembly location selectively at least a first photocrosslinkable material, in particular the present invention, as a structural material is applied to the work surface, which is irradiated surface for the purpose of material consolidation with electromagnetic radiation, and integrally with the macroscopic structure connected to form a micro- or sub-micrometer-sized substructure of the printhead assembly surface at least a second photocrosslinkable material, in particular the present invention, is applied to the working plane to form a photocrosslinkable material layer,
  • the device according to the invention is preferably based on a device known per se for the layer-by-layer production of SD structures, which is designed to carry out the SD printing technique explained in the introduction.
  • a printhead assembly is preferably provided, which is positioned relative to a working plane controlled and is connected to at least two reservoir containers in which liquid to pasty photocrosslinkable material, in particular of the present invention, each stored with different photosensitivities.
  • About the printhead assembly is preferably the respective photocrosslinkable material, in particular of the present invention, in the area of the working plane spatially selectively applicable.
  • the radiation source arrangement preferably comprises at least one laser light source, the laser beam of which can be focused by means of optical beam deflection and focusing means into a region of a photocrosslinkable material layer which can be applied to the working plane by means of the print head arrangement, and two-photon or multiphoton processes within the photocrosslinkable material layer which are used for site-selective solidification of the photocrosslinkable material Lead materials, initiated.
  • this preferred device thus combines the advantages and avoids the disadvantages associated with the known SD printing technique and the MPP method. Furthermore, this device overcomes the differences between the two process variants.
  • the materials are applied in a location-selective manner, followed by a planar irradiation of the working plane with the structures applied selectively thereto.
  • the conventional MPP process starts from a full-surface bath of liquid photocrosslinkable material at the working level, whereas solidification of the photocrosslinkable material takes place by site-selective irradiation.
  • the printhead assembly is able to realize a discharge of photocrosslinkable material in addition to a location-selective material discharge by corresponding provided on the printhead assembly individual printhead nozzles, the formation of a flat layer with a uniform Layer thickness and a planar layer surface can be carried out on the working plane.
  • the printhead assembly comprises at least two, in particular a plurality, in particular 50 to 200 pressure nozzles.
  • this provides a plurality of pressure nozzles arranged along a line through which the photocrosslinkable material can be distributed uniformly distributed.
  • the printhead assembly is preferably moved orthogonal to the linear arrangement of the individual printing nozzles relative to the working plane.
  • photocurable material in particular according to the present invention, which has optically different absorption properties.
  • the absorption properties of photocrosslinkable materials, in particular monomeric plastic materials are preferably determined by the addition of wavelength-selective photoinitiators.
  • the photoinitiators incorporated within the respective photocrosslinkable materials are capable of absorbing electromagnetic radiation of suitable wavelength, thereby causing material solidifications within the photocrosslinkable material.
  • a preferred embodiment of the radiation source arrangement for full-surface exposure to the working plane with electromagnetic radiation on a light emitting diode or diode array which emits a first wavelength spectrum in which at the same time Absorption region of the first photocrosslinkable material is applied by means of 3D printing technology on the working plane.
  • the laser light source emits laser radiation having a wavelength different from the first wavelength spectrum and absorbed by a second material applied by the inkjet process, which is thereby solidified by MPP in a substructure.
  • the physical nature of a multiphoton excitation within the photocrosslinkable material which is applied to the working plane in the context of the MPP method, also makes it possible to form a variant embodiment with a radiation source arrangement comprising a laser light source as a single radiation source.
  • a radiation source arrangement comprising a laser light source as a single radiation source.
  • two or more photon absorption processes occur only under certain conditions.
  • photosensitive material is exposed to a very high short-term irradiation intensity, as is the case when using focused pico or femtosecond short-time laser pulses.
  • optically non-linear processes which are comparable to a frequency doubling or wavelength halving, multiphoton excitations within the photocrosslinkable material in the focus area can be initiated, which locally solidify the material by means of polymerization reactions. All other material areas in which the optical conditions described above are not present represent transparent material areas for the laser radiation.
  • photo-crosslinkable material with photoinitiators adapted to the laser wavelength using 3D printing technology, then it can be moved to the working plane in a location-selective manner deposited photocrosslinkable material can be solidified by interaction with the laser light.
  • targeted use of the optically non-linear multiphoton process requires only a single light source, namely a laser, whose laser radiation is to be deposited by appropriate selection of the photocrosslinkable material to be irradiated
  • Light intensity experiences a different wavelength characteristic. If the laser beam is focused unfocused or with an expanded beam cross-section on the material surface, ie with normal or low light intensity, light absorption occurs with a suitable choice of material at the laser wavelength. If, on the other hand, the laser beam is focused and the deposited light intensity is greatly increased in this way, two or more photon effects corresponding to a light absorption with light of half the laser wavelength occur in a suitably selected material.
  • the printhead assembly is capable of the photocrosslinkable material via the multiplicity of linearly arranged printing nozzles, forming a material layer that is as homogeneous as possible in terms of material layer thickness and also also to carry out in terms of a flat or planar trained layer surface.
  • a mechanical leveling device for example in the form of a roller or a slider, the applied material is leveled and excess material removed to bring the layer to an exact nominal height.
  • a mechanical smoothing would lead to a mechanical force and, associated therewith, to a deformation or even destruction of already very fine structures produced by way of the MPP method.
  • a non-contact measuring system which detects the layer thickness and / or the layer surface properties of the photocrosslinkable material layer deposited on the working plane, for example way using optical metrology.
  • a control unit which compares the measurement signals generated by the measuring system by means of a target-actual comparison with reference data, the printhead assembly is controlled in the event of incorrectly detected layer thicknesses and / or observed layer surface textures to Nachkorrekturiller accordingly.
  • a controllable by the control unit heat source is provided, which is able to control the deposited on the working plane photocrosslinkable material layer to cause in this way an improved homogenization in particular the layer surface texture.
  • the preferred device is particularly advantageously suitable for the production of macroscopic structures, which can typically have a construction space of several cubic centimeters (cc) and which contain at least partially micro- or submicrometer-sized substructures.
  • the device has at least three reservoir units, which are each connected to the print head arrangement.
  • a first reservoir unit support material is included, which does not necessarily have to be photocrosslinkable material itself.
  • a second reservoir unit is a photocrosslinkable material, in particular of the present invention, contained, which is deposited to structure the structure by means of a location-selective material discharge together with the support material on the working plane.
  • photocrosslinkable material in particular the present invention, is provided in at least one third reservoir unit, which can be solidified in a three-dimensional micro-substructure by means of laser-beam-induced two-photon or multiphoton processes within the material layer applied by means of inkjet pressure in a spatially selective manner.
  • the 3D printing technique is used, in combination with surface solidification.
  • the support as well as the photocrosslinkable structural material, in particular the present invention can be spatially selectively applied to a common work plane via at least two different print nozzles of the print head arrangement in each case in the work plane. This is followed by a large-area exposure of the site-selectively applied material, which polymerizes the structural material and thereby solidifies. This process sequence is repeated many times in layers or layers in order to build up the macroscopic structural areas.
  • Structures which can be produced according to the invention can have feature sizes in the range from 0.1 ⁇ m to 100 ⁇ m, or typically from 0.4 ⁇ m to 100 ⁇ m.
  • the achievable smallest structural dimensions depend on the choice of the wavelength of the respective electromagnetic radiation used and the wavelength of the photons participating in the two-photon or multiphoton processes.
  • Currently available laser systems are able to produce laser light with the smallest wavelengths between 0.15 pm and 0.2 pm.
  • vascular structures originating from the biological tissue area can be reproduced and used for the transport of body fluids or nutrient media or other liquids.
  • Macrostructures can be built using the production-ready speeds commonly used for 3D inkjet printing in rapid prototyping. This typically structure resolutions of about 100 ⁇ , under optimal conditions a minimum resolution of about 10 pm achieved. Areas in which smaller structures, in particular in the range 0.5 pm to 200 pm, preferably 0.5 pm to 10 pm, preferably 0.1 pm to 200 pm, preferably 0.1 pm to 200 pm, preferably 0.5 pm to 50 pm, preferably 1 pm to 200 pm, preferably 0.1 pm to 50 pm, preferably 1 pm to 50 pm, are preferably solidified by the high-resolution MPP process. Structures are written in previously deposited by the print head material layers.
  • the MPP method can also be used for the production of structures with structure dimensions in the range of greater than 200 pm, so that an overlap of the two techniques can be used to produce structures in the transition region between microstructures and macrostructures.
  • the seamless combination of microstructuring and macrostructuring manufacturing technology enables production times for macroscopic objects with microstructured areas that are acceptable for industrial scale applications.
  • the present invention thus advantageously provides apparatuses and methods for the layered production of 3D Structures ready, which have both macroscopic dimensions of at least a few cubic centimeters in size as well as structural dimensions in the micro and / or Submikrometer Suite, ie in particular structural dimensions of a maximum, preferably smaller 10 ⁇ .
  • the 3D structures can be realized in production times that are acceptable for industrial standards. Furthermore, it is possible to produce the 3D structures with different materials and material properties in one-piece construction. The measures to be taken do not exclude the use of biocompatible materials for producing the 3D structures, so that the production of biological structures is basically possible.
  • the invention also relates to the production of three-dimensional structures, in particular tubes or tubes, in particular branched one-tube systems, with tube diameters which preferably vary from 5 mm to 0.5 ⁇ m, in particular from 5 mm to 0.1 ⁇ m, preferably the tube system from port to port has a total length of 0.5 cm to 10 cm, preferably 0.5 cm to 5 cm, in particular 1 cm to 10 cm.
  • the tube system has porous tube walls with pore diameters of 0.1 ⁇ m to 200 ⁇ m, in particular 0.5 ⁇ m to 10 ⁇ m.
  • FIG. 1 shows a schematic representation of a preferred device according to the invention, a schematic illustration of a cross section through a layered structure with macro and microstructure regions, a schematic representation of a Biofunktionalisie- tion by means of the thiol-En-Michael addition and subsequent ionic attachment of growth factors and covalent attachment of adhesion markers, a scanning electron micrograph of a capillary produced by means of MPP and the photocrosslinkable material used according to the invention according to Example 3,
  • Microstructures within an inkjet printed material layer schematic and scanning electron micrograph
  • FIG. 6 results of a vital staining and FIG. 7 a tube of material according to the invention.
  • FIG. 1 schematically shows a device for producing a 3D structure in layers with a printhead arrangement 1 which is connected to three reservoir containers 2, 3, 4.
  • a support material in the reservoir tank 3 is a photocrosslinkable Material which is spatially selectively be applied to the working plane E together with the support material by means of the printhead assembly 1.
  • the printhead assembly 1 provides at least two pressure nozzles 5, 6, by means of which the support material and the photocrosslinkable material can be dispensed in a location-selective manner on the working plane E.
  • the printhead assembly 1 is connected to another reservoir container 4 in which is stored further photocrosslinkable material whose optical absorbance differs from the optical absorbance of the photocrosslinkable material within the reservoir container 3.
  • the photocrosslinkable material originating from the reservoir container 4 serves to discharge from a plurality of pressure nozzles 7 arranged along a linear axis, which in the embodiment shown are guided in the y-direction over the working plane E.
  • the photocrosslinkable material discharged through the printing nozzles 7 is applied as a homogeneous material layer on the working plane E.
  • the device in the exemplary embodiment shown two light sources, namely a light emitting diode array LED and a laser light source L on. Both light sources are connected to a control unit R, which performs a corresponding activation of the light sources LED, L.
  • the laser beam of the laser L is focused selectively via deflection mirror SP and an optical focusing unit F into a material layer applied to the working plane E.
  • a measuring device S is provided, which is capable of detecting the surface condition of the material layer applied to the working plane A as well as its layer thickness by means of optical sensors.
  • a heat unit W intended, which can make targeted a heat input to the working level E and the deposited thereon material depositions.
  • the control unit R which also has a control function, controls or coordinates all components of the device, ie the printhead assembly 1 with the associated reservoir containers 2, 3, 4 as well as the radiation source arrangement LED, L with the associated functional units Sp, F.
  • a layered structure B which has macrostructure regions M as well as microstructure regions ⁇ .
  • the macroscopic structural areas M are realized with the 3D printing technology, in which a location-selective material application on the working level with subsequent full-area illumination and the associated complete solidification of the site-selectively applied photocrosslinkable material takes place. It is assumed that the site-selectively applied photocrosslinkable material provides a photoinitiator of a first type.
  • the photocrosslinkable material with a photoinitiator of a second type is applied over the whole area on the working plane and subsequently exposed in a location-selective manner with the aid of a focused laser beam in order to produce the micro- or sub-micrometer structures in the region ⁇ .
  • the sequence or the transition from macrostructures M to microstructures ⁇ takes place seamlessly and thus in one piece, especially as the device makes it possible to switch over immediately between the two variants of the method described from one process layer to the next.
  • FIG. 3 shows, in a first step, a reaction of the acrylate groups of a photocrosslinked material unreacted in step b) with thiol-modified heparin sulfate via the thiol-Michael addition, wherein part of the thiol groups of the modified heparin sulfate is not reacted.
  • these unreacted thiol groups are partially covalently bound with an acrylate-modified biopolymer such as heparin via the thiol-En-Michael addition.
  • Steps 1 and 2 are repeated so often (not shown in this figure) until the surface of the two- or three-dimensional photocrosslinked structure contains the modified biopolymer in the desired level or degree of coverage. Subsequently, in a step 3 to the negative charges introduced by the sulfate groups, ionic VEGF, a growth factor, and to the free acrylate groups or thiol groups via a thiol-en-Michael addition or disulfide formation RGD-SH, an adhesion anchor , bound.
  • 1.1 PTHF (1400) diacrylate 40 g of pTHF (poly (tetrahydrofuran) - average M n -1,400, Aldrich, 28.57 mmol), 5.08 g (4.8 mL, 69.3 mmol) of acrylic acid, 0.49 g (2.5 mmol) of p-toluenesulfonic acid monohydrate and 0.098 g (0.1 mmol) of hydroquinone were dissolved in 600 ml of dichlorobenzene and heated in a Dean-Stark apparatus for 48 hours under reflux until no further water separation was observed. The reaction mixture was then stirred with 30 g of K 2 C0 3 at 40 ° C for three hours and then filtered. The filtrate was extracted with 10 mM aqueous NaOH solution until the water phase became colorless was. It was then extracted to pH neutralization with distilled water. A slightly yellowish, viscous residue was obtained, which was dried under high vacuum.
  • PTHF (2000) diacrylate was prepared by the method of 1.1.
  • PTHF (2900) diacrylate was prepared by the method of 1.1.
  • PPG (2000) diacrylate was prepared by the method of 1.1. Only benzene was used as solvent instead of dichlorobenzene.
  • Toluene-2,4-diisocyanate-terminated poly (propylene glycol) (M n ⁇ 2.300 g / mol) was stirred in HEMA (10-fold excess based on the molar equivalents) at a maximum of 40 ° C until in IR the characteristic of diisocyanate bands at 2170 cm -1 were no longer visible Excess HEMA was distilled in vacuo at 60 ° C. removed. The HEMA can also not be removed and used together with PPG (2300) diurethane (meth) acrylate in a process according to the invention.
  • PTHF (1600) -diurethane (meth) acrylate was prepared by the method of 1.5.
  • toluene-2,4-diisocyanate-terminated poly (1,4-butanediol) (M n ⁇ 1,600 g / mol) was used as the starting material.
  • the polymeric crosslinker components having at least two photocrosslinkable groups were mixed at 40 ° C. with 0.5% Irgacure 184 as photoinitiator and optionally with secondary components according to Tables 1a to 1c and the viscosity was determined. These photocrosslinkable materials were irradiated and fixed in a planar manner with UV light. Following a washing protocol, WST tests (cell quantification activity assay) and confluence tests were performed to verify the biocompatibility of the photocrosslinked materials. In addition, the respective modulus of elasticity and tear strength was determined.
  • the biocompatibility is preferably achieved by suitable washing protocols of the cured polymers.
  • WST-1 proliferation tests were performed, which certify the biocompatibility of all investigated materials of the application examples from Tables 1a to 1c.
  • Cell contagions of at least 10% indicate cell-adhesive properties of non-biofunctionalized polymers.
  • the photocrosslinkable material according to number 1 from Table 1a was mixed at room temperature with 2% N 4 , N 4 -bis (4-methoxyphenyl) -N, N 4 -diphenyl-4,4'-diaminobiphenyl and a saturated solution was prepared. 20 ⁇ of the photocrosslinkable material was placed on a glass slide, so that a layer thickness of 170 ⁇ emerged.
  • This photocrosslinkable material was surface-cured by means of location-selective laser radiation with a wavelength of 532 nm via two-photon processes. The method was based on a CAD model of the three-dimensional structure to be produced, which was subdivided vertically into 75 plane sections. Each of these 75 cuts was filled with trajectories. The laser beam was guided accordingly to these predetermined trajectories, so that by this fixation, the three-dimensional structure, namely a branched Kapillargefäss with an inner diameter of 20 ⁇ and a height of 150 ⁇ , was obtained
  • endothelial cells were used after a 48-hour culture period.
  • the molecular weight of the different PTHF diacrylates (DA) has an influence on the modulus of elasticity, giving rise to soft to very soft polymers (numbers 1 to 4).
  • Table 1 lists the properties of the compositions. The selected examples all fulfill the properties according to the invention.
  • Simple patterns (such as squares) were printed using 3D inkjet printing technology. 1 - 8 layers of material were applied, followed by structuring by means of MPP. Alternatively, one or more layers of material were first applied and cured completely flat by UV irradiation. Subsequently, one or more layers of material were again applied to this layer and a structuring was produced there by means of MPP.
  • a Spectra SL-128 printhead was used. This standard print head produces droplets with an average drop size of 80 pl, which in the printed state have a diameter of approximately 80 pm to 100 pm.
  • FIG. 5 shows the selective cure by MMP within an inkjet printed layer.
  • Left in Figure 5 Schematic representation of the two-layer system.
  • Top right in FIG. 5 SEM image of the microstructured material in a printing layer after removal of the uncrosslinked material.
  • Reference numeral 1 in FIG. 5 sample carrier (glass lid)
  • the biocompatible material 11 from Table 1 was coated with a biofunctional layer of thiol-functionalized heparin (TH) and the peptide sequence arginine-glycine-aspartic acid-cysteine (RGDC) to counteract thrombogenic activity of the material and promote the adhesion of endothelial cells.
  • TH thiol-functionalized heparin
  • RGDC peptide sequence arginine-glycine-aspartic acid-cysteine
  • Human microvascular endothelial cells were isolated from human skin biopsy specimens, pre-cultured, and applied to the TH-RGDC functionalized surfaces, as well as to control surfaces (unfunctionalized polymer and commercially available standard cell culture surfaces). The cells are cultured on the materials for 48 hours. Thereafter, their vitality, morphology, confluence (cell density), metabolic activity and functionality are examined.
  • Fig. 6 shows human microvascular endothelial cells (light and gray) on A) unfunctionalized polymer B) ⁇ RGDC-functionalized polymer according to the invention and C) commercially available standard cell culture surface.
  • Cells on the functionalized material (B) show highest cell density. Except for a few cells, all cells are alive and show typical morphology. Cells on unfunctionalized material are live, but have atypical morphology and do not multiply.
  • Cells on the control standard cell culture surface (C) are alive except for single cells and with typical morphology, Fig. 6A shows no dead cells but less living ones; Figures 6B and 6C show a few isolated dead cells, many cells are alive, more in Figure 6B than in Figure 6C).
  • FIG. 7 shows tubes made of material 11 according to the invention.
  • Bottom unfunctionalized polymer without cells.
  • Middle unfunctionalized polymer after colonization with endothelial cells and cultivation in the bioreactor.
  • AlamarBlue detection of cell activity blue Alamar Blue dye is converted by vital cells to a red-violet dye. Bottom: barely implemented (blue, no cells).
  • Middle medium conversion (purple, few cells / low vitality). Above: Strong conversion (red-violet). Cells on the functionalized material show highest vitality.

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Abstract

L'invention concerne un procédé de production d'une structure à deux ou trois dimensions qui est de préférence biocompatible et biofonctionnalisée. Ladite invention concerne également la structure à deux ou trois dimensions ainsi produite, ainsi qu'un dispositif de production de ladite structure à deux ou trois dimensions.
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DE102012219691A1 (de) * 2012-10-26 2014-04-30 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Modifizierte Gelatine, Verfahren zu ihrer Herstellung und Verwendung
DE102012219691B4 (de) * 2012-10-26 2015-07-02 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Modifizierte Gelatine, Verfahren zu ihrer Herstellung und Verwendung
US11358342B2 (en) 2014-06-23 2022-06-14 Carbon, Inc. Methods of producing three-dimensional objects from materials having multiple mechanisms of hardening
US10899868B2 (en) 2014-06-23 2021-01-26 Carbon, Inc. Methods for producing footwear with materials having multiple mechanisms of hardening
US9676963B2 (en) 2014-06-23 2017-06-13 Carbon, Inc. Methods of producing three-dimensional objects from materials having multiple mechanisms of hardening
US9982164B2 (en) 2014-06-23 2018-05-29 Carbon, Inc. Polyurea resins having multiple mechanisms of hardening for use in producing three-dimensional objects
US12179435B2 (en) 2014-06-23 2024-12-31 Carbon, Inc. Methods of producing three-dimensional objects with apparatus having feed channels
US12172382B2 (en) 2014-06-23 2024-12-24 Carbon, Inc. Methods for producing three-dimensional objects
US11850803B2 (en) 2014-06-23 2023-12-26 Carbon, Inc. Methods for producing three-dimensional objects with apparatus having feed channels
US10240066B2 (en) 2014-06-23 2019-03-26 Carbon, Inc. Methods of producing polyurea three-dimensional objects from materials having multiple mechanisms of hardening
US11707893B2 (en) 2014-06-23 2023-07-25 Carbon, Inc. Methods for producing three-dimensional objects with apparatus having feed channels
US10647879B2 (en) 2014-06-23 2020-05-12 Carbon, Inc. Methods for producing a dental mold, dental implant or dental aligner from materials having multiple mechanisms of hardening
US9598606B2 (en) 2014-06-23 2017-03-21 Carbon, Inc. Methods of producing polyurethane three-dimensional objects from materials having multiple mechanisms of hardening
US10155882B2 (en) 2014-06-23 2018-12-18 Carbon, Inc. Methods of producing EPOXY three-dimensional objects from materials having multiple mechanisms of hardening
US11440266B2 (en) 2014-06-23 2022-09-13 Carbon, Inc. Methods of producing epoxy three-dimensional objects from materials having multiple mechanisms of hardening
US10968307B2 (en) 2014-06-23 2021-04-06 Carbon, Inc. Methods of producing three-dimensional objects from materials having multiple mechanisms of hardening
US11299579B2 (en) 2014-06-23 2022-04-12 Carbon, Inc. Water cure methods for producing three-dimensional objects from materials having multiple mechanisms of hardening
US11312084B2 (en) 2014-06-23 2022-04-26 Carbon, Inc. Methods for producing helmet inserts with materials having multiple mechanisms of hardening
US10647880B2 (en) 2014-06-23 2020-05-12 Carbon, Inc. Methods of producing polyurethane three-dimensional objects from materials having multiple mechanisms of hardening
WO2016139286A1 (fr) * 2015-03-03 2016-09-09 Basf Se Procédé de fabrication d'une structure tridimensionnelle par impression 3d
US11578305B2 (en) 2017-01-31 2023-02-14 Fraunhofer-Gesellschaft Zur Foerderung Der Angewandten Forschung E.V. Structured composite of matrix material and nanoparticles
WO2018141657A1 (fr) 2017-01-31 2018-08-09 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Composite structuré composé d'un matériau de matrice et de nanoparticules
DE102017101823A1 (de) 2017-01-31 2018-08-02 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Strukturiertes Komposit aus Matrixmaterial und Nanopartikeln
US10316213B1 (en) 2017-05-01 2019-06-11 Formlabs, Inc. Dual-cure resins and related methods
US10793745B2 (en) 2017-05-01 2020-10-06 Formlabs, Inc. Dual-cure resins and related methods
WO2023117656A1 (fr) * 2021-12-23 2023-06-29 Leibniz-Institut Für Neue Materialien Gemeinnützige Gmbh Composition durcissable et son utilisation

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